Hernandes Isabel S, Da Silva Haroldo C, Dos Santos Hélio F, De Almeida Wagner B
Laboratório de Química Computacional e Modelagem Molecular (LQC-MM), Departamento de Química Inorgânica, Instituto de Química, Universidade Federal Fluminense (UFF), Outeiro de São João Batista s/n, Campus do Valonguinho, Centro, Niterói 24020-141, Rio de Janeiro, Brazil.
Núcleo de Estudos em Química Computacional (NEQC), Departamento de Química, ICE, Universidade Federal de Juiz de Fora (UFJF), Campus Universitário, Martelos, Juiz de Fora 36036-330, Minas Gerais, Brazil.
J Phys Chem B. 2021 Apr 8;125(13):3321-3342. doi: 10.1021/acs.jpcb.1c00609. Epub 2021 Mar 24.
Chloroquine (CQ) and hydroxychloroquine (HCQ) have been standard antimalarial drugs since the early 1950s, and very recently, the possibility of their use for the treatment of COVID-19 patients has been considered. To understand the drug mode of action at the submicroscopic level (atoms and molecules), molecular modeling studies with the aid of computational chemistry methods have been of great help. A fundamental step in such theoretical investigations is the knowledge of the predominant drug molecular structure in solution, which is the real environment for the interaction with biological targets. Our strategy to access this valuable information is to perform density functional theory (DFT) calculations of H NMR chemical shifts for several plausible molecular conformers and then find the best match with experimental NMR profile in solution (since it is extremely sensitive to conformational changes). Through this procedure, after optimizing 30 trial distinct molecular structures (ωB97x-D/6-31G(d,p)-PCM level of calculation), which may be considered representative conformations, we concluded that the global minimum (named ), stabilized by an intramolecular N-H hydrogen bond, is not likely to be observed in water, chloroform, and dimethyl sulfoxide (DMSO) solution. Among fully optimized conformations (named to , and and ), we found (having no intramolecular H-bond) as the most probable structure of CQ and HCQ in water solution, which is a good approximate starting geometry in drug-receptor interaction simulations. On the other hand, the preferred CQ and HCQ structure in chloroform (and CQ in DMSO-) solution was assigned as , showing the solvent effects on conformational preferences. We believe that the analysis of H NMR data in solution can establish the connection between the macro level (experimental) and the sub-micro level (theoretical), which is not so apparent to us and appears to be more appropriate than the thermodynamic stability criterion in conformational analysis studies.
自20世纪50年代初以来，氯喹（CQ）和羟氯喹（HCQ）一直是标准的抗疟药物，最近，人们开始考虑将它们用于治疗新冠肺炎患者的可能性。为了在亚微观层面（原子和分子）理解药物的作用模式，借助计算化学方法进行的分子建模研究起到了很大的帮助。此类理论研究的一个基本步骤是了解溶液中主要的药物分子结构，这是与生物靶点相互作用的实际环境。我们获取这一宝贵信息的策略是对几种可能的分子构象进行密度泛函理论（DFT）计算以得到氢核磁共振（H NMR）化学位移，然后找到与溶液中实验核磁共振谱的最佳匹配（因为它对构象变化极其敏感）。通过这个过程，在优化了30种不同的试验分子结构（计算水平为ωB97x-D/6-31G(d,p)-PCM）后，这些结构可被视为代表性构象，我们得出结论，由分子内N-H氢键稳定的全局最小值（命名为 ）在水、氯仿和二甲基亚砜（DMSO）溶液中不太可能出现。在完全优化的构象（命名为 至 以及 和 ）中，我们发现 （没有分子内氢键）是CQ和HCQ在水溶液中最可能的结构，这是药物-受体相互作用模拟中一个很好的近似起始几何结构。另一方面，氯仿（以及DMSO-中的CQ）溶液中CQ和HCQ的优选结构被确定为 ，显示出溶剂对构象偏好的影响。我们认为，对溶液中H NMR数据的分析可以建立宏观层面（实验）和亚微观层面（理论）之间的联系，这对我们来说并不那么明显，而且在构象分析研究中似乎比热力学稳定性标准更合适。
